Triacylglycerols Phosphoglycerols Are Formed By Acylation Of Triose Phosphates

The major pathways of triacylglycerol and phosphoglyc-erol biosynthesis are outlined in Figure 24-1. Important substances such as triacylglycerols, phosphatidyl-choline, phosphatidylethanolamine, phosphatidylinositol, and cardiolipin, a constituent of mitochondrial membranes, are formed from glycerol-3-phosphate. Significant branch points in the pathway occur at the phosphati-date and diacylglycerol steps. From dihydroxyacetone phosphate are derived phosphoglycerols containing an ether link (—C—O—C—), the best-known of which are plasmalogens and platelet-activating factor (PAF). Glycerol 3-phosphate and dihydroxyacetone phosphate are intermediates in glycolysis, making a very important connection between carbohydrate and lipid metabolism.

Glycerol 3-phosphate -Dihydroxyacetone phosphate

Phosphatidate Plasmalogens PAF

Diacylglycerol Cardiolipin Phosphatidylinositol

Phosphatidylcholine Triacylglycerol Phosphatidylinositol

Phosphatidylethanolamine 4,5-bisphosphate

Figure 24-1. Overview of acylglycerol biosynthesis. (PAF, platelet-activating factor.)

H2C-0H Glycerol

I GLYCEROL KINASE

H2C-O-® sn-Glycerol 3-phosphate

GLYCEROL-3-PHOSPHATE DEHYDROGENASE

Dihydroxyacetone phosphate

- Glycolysis

Acyl-CoA (mainly saturated)

GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE

H2C-I

O II

OH H

H2C-OH

h2c-

1-Acylglycerol-3-phosphate (lysophosphatidate)

Choline Phosphatidylcholine h2c-o-(p) I

Choline Phosphatidylcholine

- Phosphatidylserine

Figure 24-2. Biosynthesis of triacylglycerol and phospholipids. (CD, Monoacylglycerol pathway; CD, glycerol phosphate pathway.) Phosphatidylethanolamine may be formed from ethanolamine by a pathway similar to that shown for the formation of phosphatidylcholine from choline.

O II

O H2C-O-C-R3 Triacyglycerol

(-CHs)s Serine

Inositol Phosphatidylinositol

O H2C-O-®-Inositol-® Phosphatidylinositol 4-phosphate ATP -

I KINASE I ADP A

- Phosphatidylserine

Figure 24-2. Biosynthesis of triacylglycerol and phospholipids. (CD, Monoacylglycerol pathway; CD, glycerol phosphate pathway.) Phosphatidylethanolamine may be formed from ethanolamine by a pathway similar to that shown for the formation of phosphatidylcholine from choline.

Phosphatidylinositol 4,5-bisphosphate

Ethanolamine

Phosphatidate Is the Common Precursor in the Biosynthesis of Triacylglycerols, Many Phosphoglycerols, & Cardiolipin

Both glycerol and fatty acids must be activated by ATP before they can be incorporated into acylglycerols. Glycerol kinase catalyzes the activation of glycerol to ^'glycerol 3-phosphate. If the activity of this enzyme is absent or low, as in muscle or adipose tissue, most of the glycerol 3-phosphate is formed from dihydroxyace-tone phosphate by glycerol-3-phosphate dehydrogenase (Figure 24-2).

A. Biosynthesis of Triacylglycerols_

Two molecules of acyl-CoA, formed by the activation of fatty acids by acyl-CoA synthetase (Chapter 22), combine with glycerol 3-phosphate to form phosphati-date (1,2-diacylglycerol phosphate). This takes place in two stages, catalyzed by glycerol-3-phosphate acyl-transferase and 1-acylglycerol-3-phosphate acyltrans-ferase. Phosphatidate is converted by phosphatidate phosphohydrolase and diacylglycerol acyltransferase to 1,2-diacylglycerol and then triacylglycerol. In intestinal mucosa, monoacylglycerol acyltransferase converts monoacylglycerol to 1,2-diacylglycerol in the monoacylglycerol pathway. Most of the activity of these enzymes resides in the endoplasmic reticulum of the cell, but some is found in mitochondria. Phosphati-date phosphohydrolase is found mainly in the cytosol, but the active form of the enzyme is membrane-bound.

In the biosynthesis of phosphatidylcholine and phosphatidylethanolamine (Figure 24-2), choline or ethanolamine must first be activated by phosphoryla-tion by ATP followed by linkage to CTP. The resulting CDP-choline or CDP-ethanolamine reacts with 1,2-di-acylglycerol to form either phosphatidylcholine or phosphatidylethanolamine, respectively. Phosphatidyl-serine is formed from phosphatidylethanolamine directly by reaction with serine (Figure 24-2). Phos-phatidylserine may re-form phosphatidylethanolamine by decarboxylation. An alternative pathway in liver enables phosphatidylethanolamine to give rise directly to phosphatidylcholine by progressive methylation of the ethanolamine residue. In spite of these sources of choline, it is considered to be an essential nutrient in many mammalian species, but this has not been established in humans.

The regulation of triacylglycerol, phosphatidyl-choline, and phosphatidylethanolamine biosynthesis is driven by the availability of free fatty acids. Those that escape oxidation are preferentially converted to phos-pholipids, and when this requirement is satisfied they are used for triacylglycerol synthesis.

A phospholipid present in mitochondria is cardiolipin (diphosphatidylglycerol; Figure 14-8). It is formed from phosphatidylglycerol, which in turn is synthesized from CDP-diacylglycerol (Figure 24-2) and glycerol 3-phosphate according to the scheme shown in Figure 24-3. Cardiolipin, found in the inner membrane of mitochondria, is specifically required for the functioning of the phosphate transporter and for cytochrome oxidase activity.

B. Biosynthesis of Glycerol Ether Phospholipids

This pathway is located in peroxisomes. Dihydroxyace-tone phosphate is the precursor of the glycerol moiety of glycerol ether phospholipids (Figure 24-4). This compound combines with acyl-CoA to give 1-acyldihy-droxyacetone phosphate. The ether link is formed in the next reaction, producing 1-alkyldihydroxyacetone phosphate, which is then converted to 1-alkylglycerol 3-phosphate. After further acylation in the 2 position, the resulting 1-alkyl-2-acylglycerol 3-phosphate (analogous to phosphatidate in Figure 24-2) is hydrolyzed to give the free glycerol derivative. Plasmalogens, which comprise much of the phospholipid in mitochondria, are formed by desaturation of the analogous 3-phos-phoethanolamine derivative (Figure 24-4). Platelet-activating factor (PAF) (1-alkyl-2-acetyW«-glycerol-3-phosphocholine) is synthesized from the corresponding 3-phosphocholine derivative. It is formed by many blood cells and other tissues and aggregates platelets at concentrations as low as 10-11 mol/L. It also has hy-potensive and ulcerogenic properties and is involved in a variety of biologic responses, including inflammation, chemotaxis, and protein phosphorylation.

CDP-Diacyl-glycerol sn-Glycerol 3-phosphate

Phosphatidylglycerol phosphate H2O

Phosphatidylglycerol

Cardiolipin (diphosphatidylglycerol)

Figure 24-3. Biosynthesis of cardiolipin.

Acyl-CoA

ACYL-TRANSFERASE

Dihydroxyacetone phosphate

1-Acyldihydroxyacetone phosphate h2c-o-(p)

1-Alkyldihydroxyacetone phosphate

REDUCTASE

1-Alkylglycerol 3-phosphate

Acyl-CoA

ACYL-TRANSFERASE

CDP-CMP Ethanolamine

1-Alkyl-2-acylglycerol 3-phosphoethanolamine

CDP-ETHANOLAMINE: ALKYLACYLGLYCEROL PHOSPHOETHANOLAMINE TRANSFERASE

PHOSPHOHYDROLASE

Cyt b5

DESATURASE

1-Alkyl-2-acylglycerol

CDP-choline~

CDP-CHOLINE: ALKYLACYLGLYCEROL PHOSPHOCHOLINE TRANSFERASE

1-Alkyl-2-acylglycerol 3-phosphate

■ Alkyl, diacyl glycerols

1-Alkenyl-2-acylglycerol 3-phosphoethanolamine plasmalogen

1-Alkyl-2-acylglycerol 3-phosphocholine

Acetyl-CoA

Acetyl-CoA

ACETYLTRANSFERASE

1-Alkyl-2-lysoglycerol 3-phosphocholine

ACETYLTRANSFERASE

Choline

1-Alkyl-2-acetylglycerol 3-phosphocholine PAF

Figure 24-4. Biosynthesis of ether lipids, including plasmalogens, and platelet-activating factor (PAF). In the de novo pathway for PAF synthesis, acetyl-CoA is incorporated at stage *, avoiding the last two steps in the pathway shown here.

Phospholipases Allow Degradation & Remodeling of Phosphoglycerols

Although phospholipids are actively degraded, each portion of the molecule turns over at a different rate— eg, the turnover time of the phosphate group is different from that of the 1-acyl group. This is due to the presence of enzymes that allow partial degradation followed by resynthesis (Figure 24-5). Phospholipase A2 catalyzes the hydrolysis of glycerophospholipids to form a free fatty acid and lysophospholipid, which in turn may be reacylated by acyl-CoA in the presence of an acyltransferase. Alternatively, lysophospholipid (eg, ly-

solecithin) is attacked by lysophospholipase, forming the corresponding glyceryl phosphoryl base, which in turn may be split by a hydrolase liberating glycerol 3-phosphate plus base. Phospholipases A1, A2, B, C, and D attack the bonds indicated in Figure 24-6. Phospholipase A2 is found in pancreatic fluid and snake venom as well as in many types of cells; phospholipase C is one of the major toxins secreted by bacteria; and phospholipase D is known to be involved in mammalian signal transduction.

Lysolecithin (lysophosphatidylcholine) may be formed by an alternative route that involves lecithin: cholesterol acyltransferase (LCAT). This enzyme,

H COH

HC-OH

NADPH, O

HoC-O

Choline

H2C-O-(g — Choline Phosphatidylcholine h2o

Acyl-CoA

H2C-O-(g — Choline Phosphatidylcholine h2o

PHOSPHOLIPASE A2

Acyl-CoA

H2C-O-® —Choline Lysophosphatidylcholine (lysolecithin)

LYSOPHOSPHOLIPASE

H2C-O-® —Choline Glycerylphosphocholine

GLYCERYLPHOSPHOCHOLINE HYDROLASE

+ Choline sn-Glycerol 3-phosphate

Figure 24-5. Metabolism of phosphatidylcholine (lecithin).

PHOSPHOLIPASE B PHOSPHOLIPASE A,

O

h2c-

r2— c -

PHOSPHOLIPASE A2

PHOSPHOLIPASE D

PHOSPHOLIPASE A2

PHOSPHOLIPASE C

Figure 24-6. Sites of the hydrolytic activity of phos-pholipases on a phospholipid substrate.

found in plasma, catalyzes the transfer of a fatty acid residue from the 2 position of lecithin to cholesterol to form cholesteryl ester and lysolecithin and is considered to be responsible for much of the cholesteryl ester in plasma lipoproteins. Long-chain saturated fatty acids are found predominantly in the 1 position of phospholipids, whereas the polyunsaturated acids (eg, the precursors of prostaglandins) are incorporated more into the 2 position. The incorporation of fatty acids into lecithin occurs by complete synthesis of the phospho-lipid, by transacylation between cholesteryl ester and lysolecithin, and by direct acylation of lysolecithin by acyl-CoA. Thus, a continuous exchange of the fatty acids is possible, particularly with regard to introducing essential fatty acids into phospholipid molecules.

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